EP2773754B1 - Compounds for use in the treatment of T-cell mediated diseases - Google Patents

Compounds for use in the treatment of T-cell mediated diseases Download PDF

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EP2773754B1
EP2773754B1 EP12845460.0A EP12845460A EP2773754B1 EP 2773754 B1 EP2773754 B1 EP 2773754B1 EP 12845460 A EP12845460 A EP 12845460A EP 2773754 B1 EP2773754 B1 EP 2773754B1
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methyl
oxo
indole
pyridinyl
carboxamide
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English (en)
French (fr)
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EP2773754A4 (en
EP2773754A1 (en
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Anna K. BASSIL
Soren BEINKE
Rabinder Kumar Prinjha
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GlaxoSmithKline Intellectual Property No 2 Ltd
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GlaxoSmithKline Intellectual Property No 2 Ltd
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Definitions

  • This invention relates to compounds which inhibit EZH2/EZH1 and their uses for treating T cell mediated inflammatory immune diseases.
  • Posttranslational modifications of proteins play a critical role in the regulation of signal transduction from receptors, chromatin remodelling and gene transcription. These modifications include acetylation, methylation, phosphorylation, ubiquitinylation, SUMOylation.
  • EZH (enhancer of zeste homolog) 1 and 2 are the catalytic subunits of the Polycomb Repressor Complex 2 (PRC2) and exhibit methyltransferase activity that can catalyse the methylation of lysine amino acids ( Margueron R, Reinberg D:The Polycomb complex PRC2 and its mark in life. Nature. 2011 Jan 20;469 (7330):343-9 )
  • Histone H3 is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells. Chromatin is the complex combination of DNA and protein that makes up chromosomes. It is found inside the nuclei of eukaryotic cells and is divided between heterochromatin (condensed) and euchromatin (extended).
  • the basic building blocks of chromatin are nucleosomes, each of which is composed of 146 base pairs of DNA wrapped around a histone octamer that consists of 2 copies of each H2A, H2B, H3 and H4.
  • the functions of chromatin are to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis, and to serve as a mechanism to control gene expression and DNA replication.
  • the chromatin structure is controlled by a series of post translational modifications to histone proteins, notably histones H3 and H4, and most commonly within the "histone tails" which extend beyond the core nucleosome structure.
  • H3K27me3 Binding of enzymes and adaptor proteins to posttranslational modification in histone tails regulates chromatin dynamics and gene expression.
  • H3K27me3 is thought to silence gene expression by recruiting histone deacetylases to the modified nucleosomes and stall transcriptional elongation by polymerase II.
  • inhibition of the enzymatic activity of EZH1 and EZH2 may result in a loss of H3K27me3 and up-regulation of target genes.
  • the reorganization of the actin cytoskeleton critically contributes to T cell responses by facilitating the interaction of T cells with antigen presenting cells or target cells.
  • actin remodelling plays an important role in T cell migration and motility during their recruitment to the sites of inflammation.
  • a fraction of EZH2 protein was found to localize to the cytoplasm of T cells and to interact with the small GTPase VAV1, which is involved in actin remodelling.
  • Genetic elimination of EZH2 resulted in impaired polymerization of actin in TCR stimulated T cells or at the T cell - antigen presenting cell interphase.
  • actin polymerization induced by EZH2 over-expression was dependent on the methytransferase activity of EZH2. Proliferation of T cells in response to TCR was also impaired in the absence of EZH2.
  • inhibition of EZH1 and / or EZH2 may suppress the activation of T cells.
  • Mature T cell respond to foreign peptide antigens in the presence of appropriate co-stimulation by antigen presenting cells. They have the capability to discriminate between self and non self as a consequence of the selection of a TCR repertoire specific for foreign antigens in the thymus, tolerance induction of self reactive T cell clones in the periphery, and control of T cell activation by self antigen by regulatory T cells.
  • T cells provide protection against different classes of pathogens by mediating distinct types of adaptive immune responses as a consequence of the expression of distinct sets of cytokines and other soluble and cell-bound products. In addition, they act as principle amplifiers and inducers of the appropriate inflammatory and effector responses in cells of the innate immune system and nonimmune cells.
  • CD8 T cells can lyse cells bearing intracellular pathogens but may also contribute to tissue damage and secrete pro-inflammatory cytokines, e.g. TNF and IFNg.
  • CD4 T cells can have diverse functions in inflammation depending on their specific cytokine expression profiles.
  • CD4 + Th1 cells are important for the clearance of intracellular pathogens but also play a critical role in inflammation through the expression of TNF and IFNg.
  • IL-17 expressing CD4 + Th17 cells which mediate neutrophilia and tissue remodelling and repair, have also been shown to be involved in many inflammatory conditions.
  • CD4 + Th2 cells are involved in allergic responses by expressing IL-13, IL-5 and IL-4 which mediate airway hyper reactivity, eosinophil recruitment and IgE production.
  • T cell activation is considered central to many inflammatory immune diseases. Accordingly, compounds that inhibit EZH1 and / or EZH2 activity and suppress T cell activation would be useful for the treatment of T cell mediated inflammatory immune diseases.
  • Inhibitors of EZH1/EZH2 that are useful in treating cancer have been reported in PCT applications PCT/US2011/035336 , PCT/US2011/035340 , and PCT/US2011/035344 .
  • the invention relates to a compound or a pharmaceutically acceptable salt thereof which inhibits EZH2 and/or EZH1 for use in treating T cell mediated inflammatory immune diseases or T cell mediated hypersensitivity diseases.
  • the invention relates to the use of a compound or a pharmaceutically acceptable salt thereof which inhibits EZH2 and/or EZH1 in the manufacture of a medicament for treating T cell mediated inflammatory immune diseases or T cell mediated hypersensitivity diseases.
  • the present invention relates to a compound for use in treating T cell mediated inflammatory immune diseases or a T cell mediated hypersensitivity diseases, wherein the compound is selected from the group comprising:
  • an “effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • a method may comprise administering to a human, e.g. a human in need thereof, a therapeutically effective amount of an agent described herein.
  • a compound or a pharmaceutically acceptable salt thereof which inhibits EZH2 and/or EZH1 i.e. an EZH2 and/or EZH1 inhibitor
  • a compound or a pharmaceutically acceptable salt thereof which inhibits EZH2 and/or EZH1 i.e. an EZH2 and/or EZH1 inhibitor
  • Inflammation represents a group of vascular, cellular and neurological responses to trauma. Inflammation can be characterised as the movement of inflammatory cells such as monocytes, neutrophils and granulocytes into the tissues. This is usually associated with reduced endothelial barrier function and oedema into the tissues. Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A cascade of biochemical event propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells which are present at the site of inflammation and is characterised by simultaneous destruction and healing of the tissue from the inflammatory process.
  • Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues.
  • a cascade of biochemical event propag
  • inflammation When occurring as part of an immune response to infection or as an acute response to trauma, inflammation can be beneficial and is normally self-limiting. However, inflammation can be detrimental under various conditions. This includes the production of excessive inflammation in response to infectious agents, which can lead to significant organ damage and death (for example, in the setting of sepsis). Moreover, chronic inflammation is generally deleterious and is at the root of numerous chronic diseases, causing severe and irreversible damage to tissues. In such settings, the immune response is often directed against self-tissues (autoimmunity), although chronic responses to foreign entities can also lead to bystander damage to self tissues.
  • autoimmunity autoimmunity
  • the aim of anti-inflammatory therapy is therefore to reduce this inflammation, to inhibit autoimmunity when present and to allow for the physiological process or healing and tissue repair to progress.
  • the agents may be used to treat inflammation of any tissue and organs of the body, including musculoskeletal inflammation, vascular inflammation, neural inflammation, digestive system inflammation, ocular inflammation, inflammation of the reproductive system, and other inflammation, as exemplified below.
  • Musculoskeletal inflammation refers to any inflammatory condition of the musculoskeletal system, particularly those conditions affecting skeletal joints, including joints of the hand, wrist, elbow, shoulder, jaw, spine, neck, hip, knew, ankle, and foot, and conditions affecting tissues connecting muscles to bones such as tendons.
  • musculoskeletal inflammation examples include arthritis (including, for example, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, arthritis associated with gout and pseudogout, and juvenile idiopathic arthritis), tendonitis, synovitis, tenosynovitis, bursitis, fibrositis (fibromyalgia), epicondylitis, myositis, and osteitis (including, for example, Paget's disease, osteitis pubis, and osteitis fibrosa cystic).
  • arthritis including, for example, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, arthritis associated with gout and pseudogout, and juvenile idiopathic arthritis
  • tendonitis synovitis
  • tenosynovitis bursitis
  • fibrositis fibromyalgia
  • epicondylitis myos
  • Ocular inflammation refers to inflammation of any structure of the eye, including the eye lids.
  • ocular inflammation which may be treated in this invention include blepharitis, blepharochalasis, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis, trichiasis, and uveitis.
  • inflammation of the nervous system examples include encephalitis, Guillain-Barre syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis and schizophrenia.
  • inflammation of the vasculature or lymphatic system examples include arthrosclerosis, arthritis, phlebitis, vasculitis, and lymphangitis.
  • Examples of inflammatory conditions of the digestive system which may be treated in this invention include cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, ileitis, and proctitis.
  • Examples of inflammatory conditions of the reproductive system which may be treated in this invention include cervicitis, chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis, orchitis, salpingitis, tubo-ovarian abscess, urethritis, vaginitis, vulvitis, and vulvodynia.
  • the agents may be used to treat autoimmune conditions having an inflammatory component.
  • Such conditions include acute disseminated alopecia universalise, Behcet's disease, Chagas' disease, chronic fatigue syndrome, dysautonomia, encephalomyelitis, ankylosing spondylitis, aplastic anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, diabetes mellitus type 1, giant cell arteritis, goodpasture's syndrome, Grave's disease, Guillain-Barre syndrome, Hashimoto's disease, Henoch-Schönlein purpura, Kawasaki's disease, lupus erythematosus, microscopic colitis, microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, opsocionus myoclonus syndrome, optic neuritis, ord's thyroiditis,
  • the agents may be used to treat T-cell mediated hypersensitivity diseases having an inflammatory component.
  • T-cell mediated hypersensitivity diseases having an inflammatory component.
  • Such conditions include contact hypersensitivity, contact dermatitis (including that due to poison ivy), uticaria, skin allergies, respiratory allergies (hayfever, allergic rhinitis) and gluten-sensitive enteropathy (Celliac disease).
  • inflammatory conditions which may be treated in this invention include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, ulceris, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, percarditis, peritonoitis, pharyngitis, pleuritis, pneumonitis, prostatistis, pyelonephritis, and stomatisi, transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts, and heart valve xengrafts, sewrum sickness, and graft vs host disease), acute pan
  • Preferred treatments include any one of treatment of transplant rejection, psoriatic arthritis, multiple sclerosis, Type 1 diabetes, asthma, systemic lupus erythematosis, chronic pulmonary disease, and inflammation accompanying infectious conditions (e.g., sepsis).
  • the salts of the compounds for use in the inevntion are pharmaceutically acceptable salts.
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention.
  • Salts of the compounds of the present invention may comprise acid addition salts.
  • the salts are formed from pharmaceutically acceptable inorganic and organic acids.
  • suitable acid salts include maleic, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, perchloric, fumic, acetic, propionic, succinic, glycolic, formic, lactic, aleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methansulfonic (mesylate), naphthalene-2-sulfonic, benzenesulfonic, hydroxynaphthoic, hydroiodic, malic, teroic, tannic, and the like.
  • salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, a
  • salts which are not pharmaceutically acceptable, may be useful in the preparation of compounds for use in this invention.
  • These salts such as oxalic or trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
  • compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association a compound of formal (I) with the carrier(s) or excipient(s).
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds for use in this invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of a compound of formula (I).
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit pharmaceutical compositions for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the pharmaceutical compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • compositions may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • a therapeutically effective amount of a compound for use in this invention will depend upon a number of factors including, for example, the age and weight of the intended recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant prescribing the medication.
  • an effective amount of a compound of formula (I) for the treatment of anemia will generally be in the range of 0.001 to 100 mg/kg body weight of recipient per day, suitably in the range of .01 to 10 mg/kg body weight per day.
  • the actual amount per day would suitably be from 7 to 700 mg and this amount may be given in a single dose per day or in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt or solvate, etc. may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.
  • the present compounds are automatically named by computer software, eg. ISISdraw, ChemDraw, or eLNB.
  • computer software eg. ISISdraw, ChemDraw, or eLNB.
  • the compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention as prepared are given in the examples.
  • the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. Also included in the present invention are fully or partially deuterated forms of the present compounds.
  • a compound When a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994 ).
  • Preparative normal phase silica gel chromatography was carried out using either a Teledyne ISCO CombiFlash Companion instrument with RediSep or ISCO Gold silica gel cartridges (4 g-330 g), or an Analogix IF280 instrument with SF25 silica gel cartridges (4 g - 3-00g), or a Biotage SP1 instrument with HP silica gel cartridges (10g - 100 g).
  • Purification by reverse phase HPLC was conducted using a YMC-pack column (ODS-A 75x30mm) as solid phase, unless otherwise noted.
  • a mobile phase of 25mL/min A (acetonitrile-0.1%TFA) : B (water-0.1% TFA), 10-80% gradient A (10 min) was utilized with UV detection at 214 nM, unless otherwise noted.
  • a PE Sciex API 150 single quadrupole mass spectrometer (PE Sciex, Thornhill, Ontario, Canada) was operated using electrospray ionization in the positive ion detection mode.
  • the nebulizing gas was generated from a zero air generator (Balston Inc., Haverhill, MA, USA) and delivered at 65 psi and the curtain gas was high purity nitrogen delivered from a Dewar liquid nitrogen vessel at 50 psi.
  • the voltage applied to the electrospray needle was 4.8 kV.
  • the orifice was set at 25 V and mass spectrometer was scanned at a rate of 0.5 scan/sec using a step mass of 0.2 amu and collecting profile data.
  • Method A LCMS Method A LCMS. Samples were introduced into the mass spectrometer using a CTC PAL autosampler (LEAP Technologies, Carrboro, NC) equipped with a hamilton 10 uL syringe which performed the injection into a Valco 10-port injection valve.
  • the HPLC pump was a Shimadzu LC-10ADvp (Shimadzu Scientific Instruments, Columbia, MD) operated at 0.3 mL/min and a linear gradient 4.5% A to 90% B in 3.2 min. with a 0.4 min. hold.
  • the mobile phase was composed of 100% (H 2 O 0.02% TFA) in vessel A and 100% (CH 3 CN 0.018% TFA) in vessel B.
  • the stationary phase is Aquasil (C18) and the column dimensions were 1 mm x 40 mm. Detection was by UV at 214 nm, evaporative light-scattering (ELSD) and MS.
  • Method B LCMS.
  • an Agilent 1100 analytical HPLC system with an LC/MS was used and operated at 1 mL/min and a linear gradient 5% A to 100% B in 2.2 min with a 0.4 min hold.
  • the mobile phase was composed of 100% (H 2 O 0.02% TFA) in vessel A and 100% (CH 3 CN 0.018% TFA) in vessel B.
  • the stationary phase was Zobax (C8) with a 3.5 um partical size and the column dimensions were 2.1 mm x 50 mm. Detection was by UV at 214 nm, evaporative light-scattering (ELSD) and MS.
  • ELSD evaporative light-scattering
  • Method C LCMS.
  • an MDSSCIEX API 2000 equipped with a capillary column of (50 ⁇ 4.6 mm, 5 ⁇ m) was used.
  • HPLC was done on Agilent-1200 series UPLC system equipped with column Zorbax SB-C18 (50 ⁇ 4.6 mm, 1.8 ⁇ m) eluting with CH 3 CN: ammonium acetate buffer. The reactions were performed in the microwave (CEM, Discover).
  • Analytical HPLC Products were analyzed by Agilent 1100 Analytical Chromatography system, with 4.5 x 75 mm Zorbax XDB-C18 column (3.5 um) at 2 mL/min with a 4 min gradient from 5% CH 3 CN (0.1% formic acid) to 95% CH 3 CN (0.1% formic acid) in H 2 O (0.1% formic acid) and a 1 min hold.
  • the compounds of formula (I) can be made according to Scheme 1 or by analogous methods.
  • Methyl 6-bromo-1 H -indole-4-carboxylate (I) is alkylated with an alkyl halide in the presence of base (e.g. sodium hydride) or with an alcohol in the presence of (cyanomethyl)trimethylphosphonium chloride and base (e.g. sodium hydride) to give compounds of Formula II.
  • Saponification of the ester with aqueous base provides compounds of Formula III, which are coupled to various aminomethylpyridones IV utilizing standard peptide coupling reagents (e.g. EDC, HOAT, NMM) to furnish compounds of Formula V.
  • Palladium-mediated cross-coupling of various boronic acids (or boronates) with V provides compounds of Formula VI.
  • reaction was sealed and heated at 100 °C for 2 h. The reaction was then allowed to cool to RT and sat overnight, at which time it was diluted with EtOAc, filtered through Celite, washed with EtOAc, and concentrated in vacuo.
  • Examples 3 - xx were prepared by the methods described above for Examples 1 and 2 or routine variations thereof, starting from the requisite 4-aminomethylpyridones and 6-substituuted-4-indolecarboxylates. Routine variations include, but are not limited
  • the crude compound was purified by column chromatography over silica gel (100-200 mesh, eluent: 0-10% MeOH: DCM), and the obtained product was further triturated with diethyl ether (100 mL) to afford the title compound as an off white solid (1.2 g, 50%).
  • the contents were stirred at room temperature for 32 h, and then slowly diluted into 220 mL of ice-water with stirring. The contents were stirred for 10 min, and then allowed to stand for an additional 10 min. The contents were filtered and the filtered solid was washed with additional water (50 mL). The solid was then air dried for 10 min, and then in a vacuum oven at 50 °C for 23 h total. The product was collected as 1.75 g (87%).
  • the suspension was stirred under N 2 degassing for 10 min., and then added PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.028 g, 0.034 mmol).
  • the reaction vial was sealed, placed into a heat block at 95 °C, and stirred for 1.5 h. The contents were removed from heating and allowed to cool to room temperature. The aq layer was removed from bottom of the reaction vial via pipette.
  • the reaction mixture was diluted into EtOAc (20 mL) followed by addition of 0.2 g each of Thiol-3 silicycle resin and silica gel. The volatiles were removed in vacuo and the residue dried on hi-vac for 1 h.
  • the suspension was stirred under N 2 degassing for 10 min., and then added PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.028 g, 0.034 mmol).
  • the reaction vial was sealed, placed into a heat block at 95 °C, and stirred for 1.5 h. The contents were removed from heating and allowed to cool to room temperature. The aq layer was removed from bottom of the reaction vial via pipette.
  • the reaction mixture was diluted into EtOAc (20 mL) followed by addition of 0.2 g each of Thiol-3 silicycle resin and silica gel. The volatiles were removed in vacuo and the residue dried on hi-vac for 1 h.
  • the contents were purified by silica gel chromatography (dry loaded, eluent: A:Dichloromethane, B: 10% (2M Ammonia in Methanol) in Chloroform ; Gradient B: 8-95%).
  • the obtained solid was concentrated from TBME to afford a foam, and was dried in vacuum oven at 45 °C for 18 h.
  • the product was collected as 116 mg (65%).
  • the solid was purified using column chromatography (silica gel, 0 to 15% (9:1 MeOH/NH4OH)/CH2Cl2) to give 1-isopropyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indole-4-carboxamide (51 mg, 84%) as off-white solid.
  • Examples 287 - 288 were prepared by the methods described above for Example 286, or routine variations thereof, starting from the requisite alkylester: Ex Structure Name 1 H NMR (400 MHz, DMSO- d 6 ) ⁇ ppm MS(E S) [M+H] + 287 3-[3-methyl-1-(1-methylethyl)-4-( ⁇ [(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]amin o ⁇ carbonyl)-1H-indol-6-yl]benzoic acid 13.07 (br. s., 1 H) 11.49 (br.
  • Examples 290 - 295 were prepared by the methods described above for Example 289, or routine variations thereof, starting from the requisite 6-haloindole, alkene, or CBz-protected amine: Ex Structure Name 1 H NMR (400 MHz, DMSO- d 6 ) ⁇ ppm MS(E S) [M+H] + 290 N-((4-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-indole-4-carboxamide 11.60 (br.
  • the vial was sealed and heated at 120 °C for 3 h, at which time it was diluted with water (50 ml). The mixture was extracted with 30%THF/EtOAc (2x) (needed to warm to break up emulsion). Combined organics, dried over magnesium sulfate, filtered through Celite, and concentrated.
  • the mixture was purified using reverse-phase HPLC (Gemini 5u C18(2) 100A, AXIA; 30x100 mm 5 micron; 30mL/min, 8%ACN/H2O, 0.1% formic acid to 38% ACN/H2O, 0.1% formic acid) to give the title compound (52 mg, 55%) as an off-white solid.
  • Reaction mixture was concentrated under reduced pressure, diluted with water (20 mL) and washed the resulting aqueous layer with diethyl ether (2x15 mL).
  • the aqueous layer was basified with (pH ⁇ 8) with saturated aqueous NaHCO 3 solution and extracted with dichloromethane (3x20 mL).
  • the combined organic layer was washed with brine solution (2x25 mL) and concentrated.
  • PdCl2(dppf)-CH2Cl2 adduct 14.67 mg, 0.018 mmol
  • sodium bicarbonate 45.3 mg, 0.539 mmol
  • DME 1,2-Dimethoxyethane
  • the vial was sealed and the reaction was heated to 85 °C for 1 hr. The reaction was cooled and evaporated.
  • Examples 326 - 334 were prepared by the methods described above for Example 325, or routine variations thereof, using the requisite amine: Ex Structure Name 1 H NMR (400 MHz, DMSO- d 6 ) ⁇ ppm MS(E S) [M+H] + 326 N-((6-amino-4-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxamide 10.62 (br.
  • Examples 348 - 350 were prepared by the methods described above for Example 347, or routine variations thereof, using the requisite amine: Ex Structure Name 1 H NMR (400 MHz, DMSO- d 6 ) ⁇ ppm MS(E S) [M+H] + EZH 2 plC5 0 348 6-(6- ⁇ [(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl ⁇ -3-pyridinyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxamide 11.48 (br.
  • the reaction was purified by silica gel chromatography (Analogix, SF25-60g, 0 to 50% CH 2 Cl 2 / 20%(5% NH 4 OH in MeOH) in CH 2 Cl 2 ). The last fraction contained the desired product and was combined and evaporated to dryness. Trituration with hexanes, filtration and drying under vacuum gave the methyl ester product (0.25 g, 0.65 mMol, 41%) as an off-white solid.
  • Examples 358 - 366 were prepared following the general methods described above and/or well established synthetic procedures: Ex Structure Name 1 H NMR (400 MHz, DMSO- d 6 ) ⁇ ppm MS(E S) [M+H] + EZH 2 plC5 0 358 [4-( ⁇ [(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]ami no ⁇ carbonyl)-3-methyl-1-(1-methylethyl)-1H-indol-6-yl]boronic acid 11.48 (br.
  • the first fraction contained a significant amount of the desbromo product
  • the second fraction was a mixture of unknowns
  • the last fraction contained product (Note; opposite order from the TLC).
  • the product fractions were combined, evaporated to dryness under vacuum, triturated with hexanes, filtered and dried under vacuum to give the product methyl 2-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (148 mg, 0.362 mmol, 33.7% yield) as a white solid.
  • 6-Cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (0.35 g, 2.01 mmol) was added to methanol (20 mL) and the stirred contents cooled to -10 °C. Next was added di-tert-butyloxycarbonyl (0.933 mL, 4.02 mmol) and the suspension stirred for 15 min. Next was added in NiCl 2 -6H 2 O (0.055 g, 0.201 mmol) as a solid and stirred for 5 min. Then NaBH 4 (0.532 g, 14.06 mmol) was added in 6 portions with 5 min. increments between each portion. Then the ice bath was removed and the contents were stirred with warming to room temperature overnight.
  • the reaction mixture was returned to -10 °C, followed by addition of 3 more portions of NaBH 4 (0.532 g, 14.06 mmol).
  • the ice bath was removed and the mixture stirred at room temperature for 1 h.
  • the contents were quenched by addition of diethylethylene amine (0.218 mL, 2.01 mmol) and stirred for 45 min at room temperature.
  • the volatiles were removed in vacuo and the residue suspended in EtOAc and saturated NaHCO 3 .
  • the organic layer was washed with additional NaHCO 3 .
  • the layers were separated, and the organic layer dried over MgSO 4 , filtered, and concentrated in vacuo.
  • the crude product was purified by silica gel chromatography (eluent: 10% methanol in dichloromethane).
  • 1,1 -Dimethylethyl[(6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate (0.28g, 1.006 mmol) was added to EtOAc (9 mL) and methanol (1.0 mL). The suspension was stirred at room temperature for 5 min, followed by addition of 4 M HCl in dioxane (5.03 mL, 20.12 mmol), and the contents were stirred at room temperature overnight. The volatiles were then removed i n vacuo to afford a solid. The solid was triturated with ether, filtered, and dried in a vacuum oven at 45 °C for 4 h.
  • 6-Methyl-4-[(methyloxy)methyl]-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (1.000 g, 5.61 mmol) was suspended in acetic acid (150 ml) and the solution passed through an H-cube instrument equipped with Raney-Ni cartridge at a rate of 1 mL/min at 50psi and 60 °C. After 18h. the acetic acid was removed under reduced pressure and the remaining residue was dissolved in MeOH. The methanolic solution was passed through a 0.2 ⁇ m teflon syringe filter. The methanolic filtrate was purified by reverse phase HPLC (Gemini 50x100 5 ⁇ m column. Run 1: 3 min, 90-10%.
  • reaction mixture was filtered and washed with acetic acid. The filtrate was removed under reduced pressure. The residue was washed with methanol and filtered to afford a crude mixture of 3-(aminomethyl)-6-methyl-4-(phenylmethyl)-2(1 H )-pyridinone and 3-(aminomethyl)-4-methyl-6-(phenylmethyl)-2(1 H )-pyridinone. The reaction was run in duplicate to afford a total crude recovery of 14.5 g.
  • the reamaining dark solid was triturated with a solution of (9:1) CH 2 Cl 2 , MeOH (50 mL), filtered from insoluble material, washed with (9:1) CH 2 Cl 2 , MeOH, and the filtrate evaporated to dryness under vacuum.
  • the dark solid was triturated with a solution of (1:1) EtOAc in hexanes, filtered, washed with (1:1) EtOAc in hexanes, and dried under vacuum to give a brown solid (removed a lot of fast running non-polar impurities).
  • the reaction mixture was then filtered through a Celite pad.
  • the filtrate was poured onto ice water (1 L) and extracted with diethyl ether (3 x 700 ml).
  • the combined organic layers were washed with sat NaHCO 3 , brine, and dried over anhydrous Na 2 SO 4 , filtered, and evaporated under vaccum.
  • the crude product was purified by silica gel chromatography (eluent: 10% ethyl acetate in pet ether) and afforded the title compound as a solid (80 g, 59%).
  • the alkylation of the indole nitrogen could be performed as follows: To a cooled (0 °C) suspension of methyl 6-bromo-1 H-indole-4-carboxylate (10 g, 39.4 mmol) and (cyanomethyl)(trimethyl)phosphonium chloride (14.91 g, 98 mmol) in THF (400 mL) was added 2-propanol (6.06 mL, 79 mmol), followed by sodium hydride (3.46 g, 87 mmol). The mixture was stirred at ambient temperature for 2 h, at which time LCMS showed no product formation. Heated at 50 °C for 18 h. LC/MS showed reaction complete. Filtered reaction mixture and concentrated in vacuo.

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EP12845460.0A 2011-11-04 2012-11-02 Compounds for use in the treatment of T-cell mediated diseases Active EP2773754B1 (en)

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Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9051269B2 (en) 2011-11-18 2015-06-09 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US9085583B2 (en) 2012-02-10 2015-07-21 Constellation—Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
WO2014100665A1 (en) * 2012-12-21 2014-06-26 Epizyme, Inc. 1,4-pyridone bicyclic heteroaryl compounds
WO2014151142A1 (en) 2013-03-15 2014-09-25 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US9045477B2 (en) 2013-03-15 2015-06-02 Epizyme, Inc. Substituted 6,5-fused bicyclic heteroaryl compounds
WO2015023915A1 (en) 2013-08-15 2015-02-19 Constellation Pharmaceuticals, Inc. Indole derivatives as modulators of methyl modifying enzymes, compositions and uses thereof
US9822103B2 (en) 2013-11-22 2017-11-21 Bristol-Myers Squibb Company Inhibitors of lysine methyl transferase
US20160340674A1 (en) * 2014-02-10 2016-11-24 University Of Rochester Compositions and Methods to Inhibit EZH2 for the Treatment of Cardiovascular Diseases
US20170015666A1 (en) * 2014-03-07 2017-01-19 Glaxosmithkline Intellectual Property (No.2) Limited Enhancer of zeste homolog 2 inhibitors
MX370676B (es) 2014-03-17 2019-12-19 Daiichi Sankyo Co Ltd Derivado de 1,3-benzodioxol.
RU2017118165A (ru) * 2014-10-28 2018-11-29 Глэксосмитклайн Интеллекчуал Проперти (Но.2) Лимитед Ингибиторы энхансера гомолога 2 zestes
KR20170098808A (ko) * 2014-11-06 2017-08-30 다나-파버 캔서 인스티튜트 인크. 이식편 대 숙주 질환 (gvhd)에 대한 염색질 구조를 조정하는 조성물의 용도
EP3885343A1 (en) 2014-11-06 2021-09-29 Dana-Farber Cancer Institute, Inc. Indole compounds as ezh2 inhibitors and uses thereof
AR102767A1 (es) 2014-12-05 2017-03-22 Lilly Co Eli Inhibidores de ezh2
CA2994394A1 (en) * 2015-08-03 2017-02-09 Constellation Pharmaceuticals, Inc. Ezh2 inhibitors and modulation of regulatory t-cell function
TW201718598A (zh) 2015-08-27 2017-06-01 美國禮來大藥廠 Ｅｚｈ２抑制劑
US10577350B2 (en) 2015-08-28 2020-03-03 Constellation Pharmaceuticals, Inc. Crystalline forms of (R)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide
CN105541801B (zh) * 2016-01-18 2018-07-17 常州大学 Ezh2甲基转移酶抑制剂gsk126的合成方法
WO2017184999A1 (en) 2016-04-22 2017-10-26 Dana-Farber Cancer Institute, Inc. Ezh2 inhibitors and uses thereof
US10676479B2 (en) * 2016-06-20 2020-06-09 Novartis Ag Imidazolepyridine compounds and uses thereof
MA46199A (fr) * 2016-09-07 2019-07-17 Shanghai Haihe Pharmaceutical Co Ltd Composé cyclique aromatique de pyrido à cinq éléments, son procédé de préparation et son utilisation
US10457640B2 (en) 2016-10-19 2019-10-29 Constellation Pharmaceuticals, Inc. Synthesis of inhibitors of EZH2
CN110191879A (zh) * 2017-01-25 2019-08-30 恩瑞生物医药科技（上海）有限公司 一种组蛋白甲基转移酶ezh2抑制剂、其制备方法及其医药用途
EP3823671B1 (en) 2018-07-09 2024-02-07 Fondation Asile Des Aveugles Inhibition of prc2 subunits to treat eye disorders
TWI837231B (zh) 2018-11-29 2024-04-01 日商第一三共股份有限公司 含有ｅｚｈ１／２雙重抑制劑之醫藥組合及其用途
EP3897642A4 (en) * 2018-12-21 2022-08-31 The Walter and Eliza Hall Institute of Medical Research METHODS OF TREATMENT OF INFLAMMATION
CN113773304B (zh) * 2019-02-25 2023-03-10 江苏豪森药业集团有限公司 抗耐药抗肿瘤egfr抑制剂的制备方法
CN111961034A (zh) * 2019-05-20 2020-11-20 浙江同源康医药股份有限公司 用作ret激酶抑制剂的化合物及其应用
JP7721501B2 (ja) 2019-07-31 2025-08-12 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｄ３８の阻害剤としてのヘテロ二環式アミド
WO2021035194A1 (en) 2019-08-22 2021-02-25 Juno Therapeutics, Inc. Combination therapy of a t cell therapy and an enhancer of zeste homolog 2 (ezh2) inhibitor and related methods
AU2020413313A1 (en) * 2019-12-25 2022-07-14 Nippon Shinyaku Co., Ltd. Prophylactic and/or therapeutic agent for chronic prostatitis/chronic pelvic pain syndrome
JP2024506814A (ja) 2021-01-29 2024-02-15 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｄ３８阻害剤としてのキノリン及びアザキノリン

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2584713B1 (fr) 1985-07-11 1988-09-09 Roussel Uclaf Nouveaux derives de l'indole carboxamide, leurs sels, procede et intermediaires de preparation, application a titre de medicaments et compositions les renfermant
DE10022925A1 (de) 2000-05-11 2001-11-15 Basf Ag Substituierte Indole als PARP-Inhibitoren
ATE532781T1 (de) 2003-06-19 2011-11-15 Glaxosmithkline Llc 5-(acylamino)indazol-derivate als kinase- inhibitoren
US20050059682A1 (en) * 2003-09-12 2005-03-17 Supergen, Inc., A Delaware Corporation Compositions and methods for treatment of cancer
ATE470443T1 (de) * 2004-03-11 2010-06-15 Actelion Pharmaceuticals Ltd Indol-1-yl-essigsäurederivate
WO2007053114A1 (en) * 2005-10-31 2007-05-10 S*Bio Pte Ltd Method of predicting a response to hdac inhibitors
WO2008109534A1 (en) * 2007-03-02 2008-09-12 Mdrna, Inc. Nucleic acid compounds for inhibiting ezh2 gene expression and uses thereof
US20090012031A1 (en) 2007-07-03 2009-01-08 The Regents Of The University Of Michigan EZH2 Cancer Markers
US20110064664A1 (en) * 2007-10-08 2011-03-17 The Board Of Regents Of The University Of Texas System Methods and compositions involving chitosan nanoparticles
AR070398A1 (es) 2008-02-22 2010-03-31 Gruenenthal Chemie Derivados sustituidos de indol
JP2012503651A (ja) 2008-09-26 2012-02-09 エージェンシー フォー サイエンス，テクノロジー アンド リサーチ ３−デアザネプラノシン誘導体
US9107942B2 (en) * 2008-10-31 2015-08-18 University Of Rochester Methods of diagnosing and treating fibrosis
WO2010090723A2 (en) * 2009-02-04 2010-08-12 University Of Georgia Research Foundation, Inc. Methods of inhibiting fibrogenesis and treating fibrotic disease
SMT201700245T1 (it) * 2010-05-07 2017-07-18 Glaxosmithkline Llc Indoli
WO2011140325A1 (en) * 2010-05-07 2011-11-10 Glaxosmithkline Llc Indazoles
WO2012005805A1 (en) 2010-05-07 2012-01-12 Glaxosmithkline Llc Azaindazoles
WO2012118812A2 (en) * 2011-02-28 2012-09-07 Epizyme, Inc. Substituted 6,5-fused bicyclic heteroaryl compounds

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US9242962B2 (en) 2016-01-26
RU2014122546A (ru) 2015-12-20
RU2621148C2 (ru) 2017-05-31
US20140256739A1 (en) 2014-09-11
BR112014010803A2 (pt) 2017-04-25
AU2012332297B2 (en) 2016-01-07
EP2773754A1 (en) 2014-09-10
JP2015501784A (ja) 2015-01-19
CN104039956A (zh) 2014-09-10
AU2012332297A1 (en) 2014-05-22
WO2013067296A1 (en) 2013-05-10
KR20140095073A (ko) 2014-07-31
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CA2854447A1 (en) 2013-05-10

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